Carbostyril derivatives and mood stabilizers for treating mood disorders

ABSTRACT

The pharmaceutical composition of the present invention comprises a carbostyril derivative which is a dopamine-serotonin system stabilizer and a mood stabilizer in a pharmaceutically acceptable carrier. The carbostyril derivative may be aripiprazole or a metabolite thereof. The mood stabilizer may include but is not limited to lithium, valproic acid, divalproex sodium, carbemazapine, oxcarbamazapine, zonisamide, lamotragine, topiramate, gabapentin, levetiracetam or clonazepam. These compositions are used to treat patients with mood disorders, particularly bipolar disorder with or without psychotic features, manta or mixed episodes. Methods are provided for separate administration of a carbostyril derivative and a mood stabilizer to a patient with a mood disorder.

FIELD OF THE INVENTION

The present invention provides pharmaceutical compositions comprisingcarbostyril derivatives that act as dopamine-serotonin systemstabilizers in combination with mood stabilizers in a pharmaceuticallyacceptable carrier. The present invention provides methods to treat mooddisorders such as bipolar disorder with or without psychotic features,mania or mixed episodes using the compositions of the present, inventionor by separately administering these carbostyril derivatives and moodstabilizers. The carbostyril derivatives of the present inventioninclude but are not limited to aripiprazole and metabolites thereof,such as dehydroaripiprazole. The mood stabilizers include, but are notlimited to, lithium, valproic acid, divalproex sodium, carbamazapine,oxcarbamazapine, zonisamide, lamotragine, topiramate, gabapentin,levetiracetam and clonazepam.

BACKGROUND OF THE INVENTION

The number of people with mood disorders, such as bipolar disorder withor without psychotic features, mania or mixed episodes is increasingevery year for numerous reasons. Since the period of 1950, tricyclicantidepressant drugs (e.g., imipramine, deaipramine, amitriptyline,etc.) have been developed that act to inhibit monoamine reuptake. Theyare frequently used for treating patients suffering from mood disorders.However, these drugs have side-effects, such as the following: drymouth, hazy eyes, dysuria, constipation, recognition disturbance and thelike due to anticholinergic activity; cardiovascular side-effects suchas, orthostatic hypotension, tachycardia and the like on the basis ofα₁-adrenoreceptor antagonist activity; side-effects such as, sedation,increase in the body weight and the like on the basis of histamine-H₁receptor antagonist activity.

Although the mood disorders including bipolar disorder with or withoutpsychotic features, mania or mixed episodes are heterogeneous diseases,and the causes of these diseases are not fully understood, it is likelythat the abnormalities of the monoaminergic central nervous systemcaused by serotonin, norepinephrine and dopamine and the like, and theabnormality of various hormones and peptides as well as variousstressors are causes of depression and various other mood disorders(Kubota Hasahairu et al.: “RINSHOU SEISHIN IGAKU” Vol. 29, pp 891-899,(2000)). For these reasons, even though mood stabilizer drugs, such aslithium, valproic acid, divalproex sodium, carbamazapine,oxcarbamazapine, zonisamide, lamotragine, topiramate, gabapentin,levetiracetam and clonazepam have been used, these drugs are not alwayseffective in treating all patients.

New therapeutic trials involve proposed combined therapies using anatypical antipsychotic drug, such as olanzepine or quetiapine, which areagents for treating schizophrenia (anti-psychotic drug), together withmood stabilizing drug such as valproate, lithium or divalproex ((Arch.Gen. Psychiatry, 2002 January 59:1);62-69; J Am Acad Child AdolescPsychiatry 2002 October;41(10):1216-23:)

Further, commercially available atypical antipsychotic drugs havesignificant problems relating to their safety. For example, clozapine,olanzapine and quetiapine increase body weight and enhance the risk ofdiabetes mellitus (Newcomer, J. W. (Supervised Translated by Aoba Anri):“RINSHOU SEISHIN YAKURI” Vol. 5, pp 911-925, (2002), Haupt, D. W. andNewcomer, J. W. (Translated by Fuji Yasuo and Misawa Fuminari): “RINSHOUSEISHIN YAKURI” Vol. 5, pp 1063-1082, (2002)). In fact, urgent safetyalerts have been issued in Japan relating to hyperglycemia, diabeticketoacidosis and diabetic coma caused by olanzapine and quetiapine,indicating that these drugs were subjected to dosage contraindication tothe patients with diabetes mellitus and patients having anamnesis ofdiabetes mellitus. Risperidone causes increases serum prolactin levelsand produces extrapyramidal side effects at high dosages. ziprasidoneenhances the risk of severe arrhythmia on the basis of cardio-QTcprolongation action. Further, clozapine induces agranulocytosis, so thatclinical use thereof is strictly restricted (van Kammen, D. P. (Compiledunder Supervision by Murasaki Mitsuroh) “RINSHOU SEISHIN YAKURI” Vol. 4,pp 483-492, (2001)).

Accordingly what is needed are new compositions useful for treating mooddisorders, particularly bipolar disorder with or without psychoticfeatures, mania or mixed episodes, which are efficacious and do notcause the deleterious side effects associated with prior art compounds.

SUMMARY OF THE INVENTION

The present invention solves the problems described above by providingnovel compositions and methods of using these compositions for treatingmood disorders, particularly bipolar disorder, including but not limitedto bipolar disorder I, bipolar disorder II, bipolar disorder with andwithout psychotic features, and mania, acute mania, bipolar depressionor mixed episode.

The present invention provides solutions to the above-mentionedproblems, and demonstrates that the mood disorders, such as bipolardisorder and mania, can be treated effectively by administering to apatient with such disorder a composition comprising at least onecarbostyril derivative that is a dopamine-serotonin system stabilizer incombination with at least one mood stabilizer in a pharmaceuticallyacceptable carrier. A preferred carbostyril derivative of the presentinvention that is a dopamine-serotonin system stabilizer is aripiprazoleor a metabolite thereof. Another preferred carbostyril derivative of thepresent invention that is a dopamine-serotonin system stabilizer is ametabolite of aripiprazole called dehydroaripiprazole, also known asOPC-14857. Other such metabolites of aripiprazole included within thepresent invention are shown in FIG. 8. Preferred aripiprazolemetabolites are shown in FIG. 8 indicated by the following designations:OPC-14857, DM-1458, DM-1451, DM-1452, DM-1454 and DCPP.

Aripiprazole, also called7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy)-3,4-dihydro-2(1H)-quinolinone,is a carbostyril and is useful for treating schizophrenia(JP-A-2-191256, U.S. Pat. No. 5,006,528). Aripiprazole is also known as7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy)-3,4-dihydrocarbostyril,Ability, GPC-14597, OPC-31 and BMS-337039. Aripiprazole possesses5-HT_(1A) receptor agonist activity, and is known as a useful compoundfor treating types of depression and refractory depression, such asendogenous depression, major depression, melancholia and the like (WO02/060423A2; Jordan et al U.S. Patent Application 2002/0173513A1)).Aripiprazole has activity as an agonist at serotonin receptors anddopamine receptors, and acts as an agonist or partial agonist at theserotonin 5HT_(1A) receptor and as an agonist or partial agonist at thedopamine D₂ receptor. Aripiprazole is a dopamine-serotonin systemstabilizer. Metabolites of aripiprazole are included within the scope ofthe present invention. One such metabolite of aripiprazole is calleddehydroaripiprazole. Other such metabolites of aripiprazole includedwithin the present invention are shown in FIG. 8. Preferred metabolitesare shown in FIG. 8 indicated by the following designations:OPC-14857,DM-1458,DM-1451,DM-1452, DM-1454 and DCPP.

The at least one mood stabilizer used in the present invention includesbut is not limited to the following: lithium, valproic acid, divalproexsodium, carbamazapine, oxcarbamazapine, zonisamide, lamotragine,topiramate, gabapentin, levetiracetam and clonazepam.

The novel compositions of the present invention comprising a carbostyrilderivative with activity as a dopamine-serotonin system stabilizer andat least one mood stabilizer in a pharmaceutically acceptable carriermay be combined in one dosage form, for example a pill. Alternativelythe carbostyril derivative with activity as a dopamine-serotonin systemstabilizer and the at least one mood stabilizer may be in separatedosage forms, each in a pharmaceutically acceptable carrier. Thesecompositions are administered to a patient with a mood disorder, such asbipolar disorder or mania, in an amount and dose regimen effective totreat the mood disorder.

Accordingly, it is an object of the present invention to provide acomposition useful for treating a mood disorder.

It is an object of the present invention to provide a composition usefulfor treating a mood disorder, wherein the mood disorder is bipolardisorder.

It is an object of the present invention to provide a composition usefulfor treating a mood disorder, wherein the mood disorder is mania.

It is another object of the present invention to provide a compositioncomprising a carbostyril derivative with activity as adopamine-serotonin system stabilizer and at least one mood stabilizer ina pharmaceutically acceptable carrier.

Yet another object of the present invention is to provide a compositioncomprising a carbostyril derivative with activity as adopamine-serotonin system stabilizer and at least one mood stabilizer ina pharmaceutically acceptable carrier, wherein the carbostyrilderivative is aripiprazole or a metabolite thereof.

Yet another object of the present invention is to provide a compositioncomprising a carbostyril derivative with activity as adopamine-serotonin system stabilizer and at least one mood stabilizer,wherein the carbostyril derivative with activity as a dopamine-serotoninsystem stabilizer is a metabolite of aripiprazole and is OPC-14857,DM-1458, DM-1451, DM-1452, DM-1454 or DCPP.

Yet another object of the present invention is to provide a compositioncomprising a carbostyril derivative with activity as adopamine-serotonin system stabilizer and at least one mood stabilizer,wherein the carbostyril derivative is dehydroaripiprazole.

It is an object of the present invention to provide a method fortreating a mood disorder.

It is an object of the present invention to provide a method fortreating a mood disorder wherein the mood disorder is bipolar disorder.

It is an object of the present invention to provide a method fortreating a mood disorder wherein the mood disorder is mania.

It is another object of the present invention to provide a method fortreating a mood disorder comprising administration to a patient with amood disorder of a composition comprising a carbostyril derivative withactivity as a dopamine-serotonin system stabilizer and at least one moodstabilizer in a pharmaceutically acceptable carrier.

Yet another object of the present invention is to provide a method fortreating a mood disorder comprising administration to a patient with amood disorder of a composition comprising a carbostyril. derivative withactivity as a dopamine-serotonin system stabilizer in a pharmaceuticallyacceptable carrier and a composition comprising at least one moodstabilizer in a pharmaceutically acceptable carrier.

It is another object of the present invention to provide a method fortreating a mood disorder comprising administration to a patient with amood disorder of a composition comprising a carbostyril derivative withactivity as a dopamine-serotonin system stabilizer and at least one moodstabilizer together in a pharmaceutically acceptable carrier, whereinthe carbostyril derivative is aripiprazole or a metabolite thereof.

Yet another object of the present invention is to provide a method fortreating a mood disorder comprising administration to a patient with amood disorder of a composition comprising a carbostyril derivative withactivity as a dopamine-serotonin system stabilizer in a pharmaceuticallyacceptable carrier, wherein the carbostyril derivative is aripiprazoleor a metabolite thereof, and a composition comprising at least one moodstabilizer in a pharmaceutically acceptable carrier.

Still another object of the present invention is to provide a method fortreating a mood disorder comprising administration to a patient with amood disorder of a composition comprising a carbostyril derivative withactivity as a dopamine-serotonin system stabilizer and at least one moodstabilizer in a pharmaceutically acceptable carrier, wherein thecarbostyril derivative is a metabolite of aripiprazole and isdehydroaripiprazole (OPC-14857), DM-1458, DM-1451, DM-1452, DM-1454 orDCPP.

Yet another object of the present invention is to provide a method fortreating a mood disorder comprising administration to a patient with amood disorder of a composition comprising a carbostyril derivative withactivity as a dopamine-serotonin system stabilizer in a pharmaceuticallyacceptable carrier, wherein the carbostyril derivative is a metaboliteof aripiprazole and is dehydroaripiprazole (OPC-14857), DM-1458,DM-1451, DM-1452, DM-1454 or DCPP, and a composition comprising at leastone mood stabilizer in a pharmaceutically acceptable carrier.

Yet another object of the present invention is to provide a method fortreating mood disorder comprising administration to a patient with amood disorder of a composition comprising a carbostyril derivative withactivity as a dopamine-serotonin system stabilizer and at least one moodstabilizer in a pharmaceutically acceptable carrier, wherein the mooddisorder is bipolar disorder.

Yet another object of the present invention to provide a method fortreating a mood disorder comprising administration to a patient with amood disorder of a composition comprising a carbostyril derivative withactivity as a dopamine-serotonin system stabilizer in a pharmaceuticallyacceptable carrier and a composition comprising at least one moodstabilizer in a pharmaceutically acceptable carrier, wherein the mooddisorder is bipolar disorder.

Yet another object of the present invention is to provide a method fortreating mood disorder comprising administration to a patient with amood disorder of a composition comprising a carbostyril derivative withactivity as a dopamine-serotonin system stabilizer and at least one moodstabilizer in a pharmaceutically acceptable carrier, wherein the mooddisorder is mania.

Yet another object of the present invention is to provide a method fortreating a mood disorder comprising administration to a patient with amood disorder of a composition comprising a carbostyril derivative withactivity as a dopamine-serotonin system stabilizer in a pharmaceuticallyacceptable carrier and a composition comprising at least one moodstabilizer in a pharmaceutically acceptable carrier, wherein the mooddisorder is mania.

It is another object of the present invention to provide a method fortreating mood disorder comprising administration to a patient with amood disorder of a composition comprising a carbostyril derivative withactivity as a dopamine-serotonin system stabilizer and at least one moodstabilizer in a pharmaceutically acceptable carrier.

It is another object of the present invention to provide a method fortreating mood disorder comprising separate administration to a patientwith a mood disorder of a composition comprising a carbostyrilderivative with activity as a dopamine-serotonin system stabilizer in apharmaceutically acceptable carrier, and a composition comprising atleast one mood stabilizer in a pharmaceutically acceptable carrier.

It is another object of the present invention to provide a method fortreating mood disorder comprising administration to a patient with amood disorder of a composition comprising a carbostyril derivative withactivity as a dopamine-serotonin system stabilizer and at least one moodstabilizer together with a pharmaceutically acceptable carrier, whereinthe carbostyril derivative is aripiprazole or a metabolite thereof.

Still another object of the present invention is to provide a method fortreating mood disorder comprising administration to a patient with amood disorder of a composition comprising a carbostyril derivative withactivity as a dopamine-serotonin system stabilizer and at least one moodstabilizer in a pharmaceutically acceptable carrier, wherein thecarbostyril derivative wherein the carbostyril derivative is ametabolite of aripiprazole and is OPC-14857, DM-1458, DM-1451, DM-1452,DM-1454 or DCPP.

These and other objects, advantages, and uses of the present inventionwill reveal themselves to one of ordinary skill in the art after readingthe detailed description of the preferred embodiments and the attachedclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the thermogravimetric/differential thermogram of thearipiprazole hydrate A obtained in Reference Example 4.

FIG. 2 is the ¹H-NMR spectrum (DMSO-d₆, TMS) of the aripiprazole hydrateA obtained in Reference Example 4.

FIG. 3 is the powder X-ray diffraction diagram of the aripiprazolehydrate A obtained in Reference Example 4.

FIG. 4 is the ¹H-NMR spectrum (DMSO-d₆, TMS) of the aripiprazoleanhydride crystals B obtained in Example 1.

FIG. 5 is the powder X-ray diffraction diagram of the aripiprazoleanhydride crystals B obtained in Example 1.

FIG. 6 is the thermogravimetric/differential thermogram of thearipiprazole hydrate obtained in Reference Example 3.

FIG. 7 is the powder X-ray diffraction diagram of aripiprazole hydrateobtained in Reference Example 3.

FIG. 8 is a schematic representation of the chemical structures ofaripiprazole and metabolites thereof. Some of the metabolites may beformed through other possible pathways; for example, DM-1431 could beformed by N-dealkylation of DM-1451 and DM-1459.

DETAILED DESCRIPTION

The pharmaceutical composition of the present invention comprises afirst ingredient comprising a carbostyril derivative active as adopamine-serotonin system stabilizer and a second ingredient comprisinga mood stabilizer, in a pharmaceutically acceptable carrier. Thepharmaceutical compositions of the present invention are useful intreating mood disorders, including bipolar disorder and mania.

The Pharmaceutical Composition: The First Ingredient

The first ingredient comprises a carbostyril derivative active as adopamine-serotonin system system stabilizer. Such carbostyril derivativehas activity as an agonist or partial agonist at some serotoninreceptors and some dopamine receptors, preferably as an agonist orpartial agonist at the serotonin 5HT_(1A) receptor and as an agonist orpartial agonist at the dopamine D₂ receptor. Carbostyril derivatives aredescribed in U.S. Pat. No. 5,006,528 and U.S. published patentapplication 2002/0173513A1. In one embodiment of the present invention,the carbostyril derivatives represented by the following formula (1) areused:

wherein the carbon-carbon bond between 3- and 4-positions in thecarbostyril skeleton is a single or a double bond.

In a preferred embodiment, this activity of the carbostyril derivativeis as an agonist or partial agonist at the 5HT_(1A) receptor arid anagonist or partial agonist at the dopamine D₂ receptor subtype. Inanother preferred embodiment, the carbostyril derivative to be used as afirst component in the present invention is aripiprazole, or a metabolicderivative thereof. Metabolic derivatives of aripiprazole include butare not limited to dehydroaripiprazole, also called OPC-14857. Othermetabolic derivatives of aripiprazole include but are not limited to thechemical structures shown in FIG. 8 as OPC-14857, DM-1458, DM-1451,DM-1452, DM-1454 and DCPP.

Structures and names of aripiprazole metabolites shown in FIG. 8 areprovided below.

DCPP: 1-(2,3-dichlorophenyl)pipezazine, andN-2,3-dichlorophenylpiperazine

DM-14857, OPC-14857:7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-2-(1H)-quinolinone,also called dehydroaripiprazole

DM-1451: 7-{4-[4-(2,3-dichloro-4-hydroxyphenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2-(1H)-quinolinone,and hydroxyaripiprazole

DM-1458:2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy}-butyl]-piperazin-1-yl)-phenylsulfate, and sulfated hydroxyaripiprazole

DM-1452:7-(4-(4-(2,3-dichlorophenyl)-1-piperazinyl)butoxy)-3,4-dihydro-4-hydroxy-2-(1H)-quinolinone,and benzyl hydroxyaripiprazole

DM-1434: DM-1434 is the glucuronide of DM-1451. This structure is alsoknow by the following names:

1β-(2,3-dichloro-4-(4-[4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)-butyl]-piperazin-1-yl)-phenoxy)-D-glucopyaranuronicacid,

1β-(2,3-dichloro-4-(4-[4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)-butyl]-piperazin-1-yl)-phenyl-beta)-D-glucopyaranosiduronicacid,

1β(2,3-dichloro-4-(4-[4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)-butyl]-piperazin-1-yl)-phenyl)-beta)-D-Glucuronide,

1β-(2,3-dichloro-4-(4-[4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)-butyl]-piperazin-1-yl)-phenyl-beta)-D-glucuronicacid, and glucuronide aripiprazole.

All of the aforementioned carbostyril derivatives may be used as a firstcomponent in the practice of the present invention.

Aripiprazole, also called7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy)-3,4-dihydro-2(1H)-quinolinone,is a carbostyril compound useful as the effective ingredient fortreating schizophrenia (JP-A-2-191256, U.S. Pat. No. 5,006,528).Aripiprazole is also known as7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril,Abilify, OPC-145S7, OPC-31 and BMS-337039. Aripiprazole possesses5-HT_(1A) receptor agonist activity, and is known as a useful compoundfor treating types of depression and refractory depression, such asendogenous depression, major depression, melancholia and the like (WO02/060423A2; Jordan et al. U.S. Patent Application 2002/0173513A1).Aripiprazole has activity as an agonist at serotonin receptors anddopamine receptors, and acts as an agonist or partial agonist at theserotonin 5HT_(1A) receptor and as an agonist or partial agonist at thedopamine D₂ receptor.

Aripiprazole is an antipsychotic drug having new mechanism of actionwhich is different from that of other atypical antipsychotic drugs. Theavailable typical and atypical antipsychotic drugs act as antagonists atthe dopamine-D₂ receptors. In contrast, aripiprazole acts as a partialagonist at the dopamine D₂ receptor (Ishigooka Jyunya and Inada Ken:RINSHO SEISHIN YAKORI, Vol. 4, pp 1653-1664, (2001); Burris, K. D. etal.: J. Pharmacol. Exp. Ther., 302, pp 381-389,(2002)). In addition tothe partial agonist action at dopamine-D₂ receptors, aripiprazole hasactivity as a partial agonist at the serotonin 5-HT_(1A) receptor, aswell as antagonist action serotonin 5-HT_(2A) receptors. Accordingly,aripiprazole is a drug belonging to new category defined as adopamine-serotonin system stabilizer (dopamine-serotonin nervous systemstabilizer (Burris, K. D. et al., J. Pharmacol. Exp. Ther., 302, pp381-389, 2002; Jordan, S, et al., Eur. J. Pharmacol. 441, pp 137-140,2002).

Methods of Preparing Aripiprazole

Aripiprazole and aripiprazole metabolites to be used in the presentinvention may be any of form, for example, free bases, polymorphisms ofevery type of crystal, hydrate, salt (acid addition salts, etc.) and thelike. Among of these forms, aripiprazole anhydride crystals B is apreferred form.

As to method for preparing the aripiprazole anhydride crystals B, forexample it is prepared by heating aripiprazole hydrate A as follows.

Aripiprazole Hydrate A

The aripiprazole hydrate A having the physicochemical properties shownin (1)-(5) as follows:

(1) It has an endothermic curve which is substantially identical to thethermogravimetric/differential thermal analysis (heating rate 5° C./min)endothermic curve shown in FIG. 1. Specifically, it is characterized bythe appearance of a small peak at about 71° C. and a gradual endothermicpeak around 60° C. to 120° C.

(2) It has an ¹H-NMR spectrum which is substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 2. Specifically, it hascharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H).

(3) It has a powder x-ray diffraction spectrum which is substantiallyidentical to the powder x-ray diffraction spectrum shown in FIG. 3.Specifically, it has characteristic peaks at 2θ=12.6°, 15.4°,17.3°,18.0°,18.6°, 22.5° and 24.8°.

(4) It has clear infrared absorption bands at 2951, 2822, 1692, 1577,1447, 1378, 1187, 963 and 784 cm⁻¹ on the IR (KBr) spectrum.

(5) It has a mean particle size of 50 μm or less.

Method for Preparing Aripiprazole Hydrate A

Aripiprazole hydrate A is prepared by milling conventional aripiprazolehydrate. Conventional milling methods can be used to mill conventionalaripiprazole hydrate. For example, conventional aripiprazole hydrate canbe milled in a milling machine. A widely used milling machine such as anatomizer, pin mill, jet mill or ball mill can be used. Among of these,the atomizer is preferably used.

Regarding the specific milling conditions when using an atomizer, arotational speed of 5000-15000 rpm could be used for the main axis, forexample, with a feed rotation of 10-30 rpm and a screen hole size of 1-5mm.

The mean particle size of the aripiprazole hydrate A obtained by millingmay be normally 50 μm or less, preferably 30 μm or less. Mean particlesize can be ascertained by the particle size measuring method describedhereinafter.

Aripiprazole Anhydride Crystals B

Aripiprazole anhydride crystals B of the present invention have thephysicochemical properties given in (6)-(10) below.

(6) They have an ¹H-NMR spectrum which is substantially identical to the¹H-NMR spectrum (DMSO-d₆, TMS) shown in FIG. 4. Specifically, they havecharacteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H),2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm(d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and10.00 ppm (s, 1H).

(7) They have a powder x-ray diffraction spectrum which is substantiallyidentical to the powder x-ray diffraction spectrum shown in FIG. 5.Specifically, they have characteristic peaks at 2θ=11.0°, 16.6°, 19.3°,20.3° and 22.1°.

(8) They have clear infrared absorption bands at 2945, 2812, 1678, 1627,1448, 1377, 1173, 960 and 779 cm⁻¹ on the IR (KBr) spectrum.

(9) They exhibit an endothermic peak near about 141.5° C. inthermogravimetric/differential thermal analysis (heating rate 5°C./min).

(10) They exhibit an endothermic peak near about 140.7° C. indifferential scanning calorimetry (heating rate 5° C./min).

When the small particle size is required for solid preparation, such astablets and other solid dose formulations including for example flashmelt formulations, the mean particle size is preferably 50 μm or less.

Method for Preparing Aripiprazole Anhydride Crystals B

The aripiprazole anhydride crystals B of the present invention areprepared, for example, by heating the aforementioned aripiprazolehydrate A at 90-125° C. The heating time is generally about 3-50 hours,but cannot be stated unconditionally, because it differs depending onheating temperature. The heating time and heating temperature areinversely related, so that for example when the heating time is longer,then the heating temperature is lower, and when the heating temperatureis higher then the heating time is shorter. Specifically, if the heatingtemperature of aripiprazole hydrate A is 100° C., the heating time maybe 18 hours or more, or preferably about 24 hours. If the heatingtemperature of aripiprazole hydrate A is 120° C., on the other hand, theheating time may be about 3 hours. The aripiprazole anhydride crystals Bof the present invention can be prepared with certainty by heatingaripiprazole hydrate A for about 18 hours at 100° C., and then heatingit for about 3 hours at 120° C. The aripiprazole anhydride crystals B ofthe present invention can also be obtained if the heating time isextended still further, but this method may not be economical.

When small particle size is not required for the formulation, e.g., whendrug substance is being prepared for injectable or oral solutionformulations, aripiprazole anhydride crystals B can be also obtained bythe following process.

Aripiprazole anhydride crystals B of the present invention are preparedfor example by heating conventional aripiprazole anhydride crystals at90-125° C. The heating time is generally about 3-50 hours, but cannot bestated unconditionally because it differs depending on heatingtemperature. The heating time and heating temperature are inverselyrelated, so that for example if the heating time is longer, the heatingtemperature is lower, and if the heating time is shorter, the heatingtemperature is higher. Specifically, if the heating temperature of thearipiprazole anhydride crystals is 100° C., the heating time may beabout 4 hours, and if the heating temperature is 120° C. the heatingtime may be about 3 hours.

Furthermore, aripiprazole anhydride crystals B of the present inventionare prepared for example, by heating conventional aripiprazole hydrateat 90-125° C. The heating time is generally about 3-50 hours, but cannotbe stated unconditionally because it differs depending on heatingtemperature. The heating time and heating temperature are inverselyrelated, so that for example, if the heating time is longer, the heatingtemperature is lower, and if the heating time is shorter, the heatingtemperature is higher. Specifically, if the heating temperature of thearipiprazole hydrate is 100° C., the heating time may be about 24 hours,and if the heating temperature is 120° C. the heating time may be about3 hours.

The aripiprazole anhydride crystals which are the raw material forpreparing the aripiprazole anhydride crystals B of the present inventionare prepared for example by Method A or B below.

Method A: Process for Preparing Crude Crystals of Aripiprazole

Conventional aripiprazole anhydride crystals are prepared by well-knownmethods, as described in Example 1 of Japanese Unexamined PatentPublication No. 191256/1990.7-(4-bromobutoxy)-3,4-dihydrocarbostyril, isreacted with 1-(2,3-dichlorophenyl)piperazine and the thus obtainedcrude aripiprazole crystals are re-crystallized from ethanol.

Method B: Process for Preparing Conventional Aripiprazole Anhydride

The Method 3 is described in the Proceedings of the 4th JointJapanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996). Thearipiprazole hydrate which is the raw material for preparing thearipiprazole anhydride crystals B of the present invention is preparedfor example by Method C below.

Method C: Method for Preparing Conventional Aripiprazole Hydrate

Aripiprazole hydrate is easily obtained by dissolving the aripiprazoleanhydride crystals obtained by Method A above in a hydrous solvent, andheating and then cooling the resulting solution. Using this method,aripiprazole hydrate is precipitated as crystals in the hydrous solvent.

An organic solvent containing water is usually used as the hydroussolvent. The organic solvent may be preferable one which is misciblewith water, for example an alcohol such as methanol, ethanol, propanolor isopropanol, a ketone such as acetone, an ether such astetrahydrofuran, dimethylformamide, or a mixture thereof, ethanol isparticularly desirable. The amount of water in the hydrous solvent maybe 10-25% by volume of the solvent, or preferably close to 20% byvolume.

Aripiprazole can easily form an acid addition salt with apharmaceutically acceptable acid. As to such acid, for example, aninorganic acid, such as sulfuric acid, nitric acid, hydrochloric acid,phosphoric acid, hydrobromic acid, etc.; an organic acid such as, aceticacid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, maleicacid, fumaric acid, malic acid, tartaric acid, citric acid, benzoicacid, etc. can be exemplified. Similar to aripiprazole of free forms,these acid addition salts can also be used as the active ingredientcompounds in the present invention.

The objective compound thus obtained through each one of productionsteps, is separated from the reaction system by usual separation means,and can be further purified. As to the separation and purificationmeans, for example, distillation method, solvent extraction method,dilution method, re-crystallization method, column chromatography,ion-exchange chromatography, gel chromatography, affinitychromatography, preparative thin-layer chromatography and the like canbe exemplified.

The Pharmaceutical Composition: The Second Ingredient

In the composition of the present invention, a mood stabilizer is usedas the second ingredient. Compounds which function as mood stabilizerscan be widely used as the mood stabilizers and are known to one ofordinary skill in the art.

A non-limiting list of mood stabilizers which may be used in the presentinvention includes, lithium, valproic acid, divalproex sodium,carbamazapine, oxcarbamazapine, zonisamide, lamotragine, topiramate,gabapentin, levetiracetam and clonazepam.

The mood stabilizer may be either in the form of a free base or a salt(an acid addition salt or the like). Further, the mood stabilizer may beeither a racemic modifications or R and S enantiomers. The moodstabilizers may be either a single use of one mood stabilizer, and incase of need, two or more of the mood stabilizers may be used incombination. Use of one mood stabilizer is preferred.

The mood stabilizer can easily form an acid addition salt with apharmaceutically acceptable acid. As to such acid, for example, aninorganic acid, such as sulfuric acid, nitric acid, hydrochloric acid,phosphoric acid, hydrobromic acid, etc.; an organic acid such as, aceticacid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, maleicacid, fumaric acid, malic acid, tartaric acid, citric acid, benzoicacid, etc. can be exemplified. Similar to the reuptake inhibitor of freeforms, these acid addition salts can also be used as the activeingredient compounds in the present invention.

Among the mood stabilizers, a compound having an acidic group can easilyform salt by reacting with a pharmaceutically acceptable basic compound.As to such basic compound, a metal hydroxide, for example, sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide andthe like; an alkali metal carbonate or bicarbonate, for example sodiumcarbonate, potassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate and the like; a metal alcoholate, for example sodiummethylate, potassium ethylate and the like can be exemplified.

The thus obtained salt form of mood stabilizer is separated from thereaction system by usual separation means, and can be further purified.As to the separation and purification means, for example, distillationmethod, solvent extraction method, dilution method, recrystailizationmethod, column chromatography, ion-exchange chromatography, gelchromatography, affinity chromatography, preparative thin-layerchromatography and the like can be exemplified.

Combination of the First Ingredient with the Second Ingredient

As to pharmaceutical compositions comprising a combination ofcarbostyril derivatives with activity as dopamine-serotonin stabilizers,and mood stabilizers, non-limiting examples of aripiprazole anddehydroaripiprazole are described herein. It is to be understood thatthe present invention also comprises a combination of carbostyrilderivatives with activity as dopamine-serotonin stabilizers, and moodstabilizers, wherein the carbostyril derivatives are other metabolitesof aripiprazole described herein.

When aripiprazole is combined with at least one mood stabilizer, thefollowing are non-limiting examples of such combinations:aripiprazole/lithium, aripiprazole/valproic acid,aripiprazole/divalproex sodium, aripiprazole/carbamazapine,aripiprazole/oxcarbamazapine, aripiprazole/zonisamide,aripiprazole/lamotragine, aripiprazole/topiramate,axipiprazole/gabapentin, aripiprazole/levetiracetam andaripiprazole/clonazepam. Among these combinations, the following axeparticularly preferable: aripiprazole/carbamazapine,aripiprazole/oxcarbamazapine, aripiprazole/zonisamide,aripiprazole/lamotragine, aripiprazole/topiramate,aripiprazole/gabapentin, aripiprazole/levetiracetam andaripiprazole/clonazepam. The pharmaceutical composition comprising theabove preferable combination possesses excellent efficacy. Thereforesuch composition has fewer side-effects and an excellent safety profile.

In another embodiment of the present invention, aripiprazole, or ametabolite thereof may foe combined with more than one mood stabilizer.Metabolites of aripiprazole that may be used in the present inventioninclude, but are not limited to, OPC-14857, DM-1458, DM-1451, DM-1452,DM-1454 and DCPP as shown in FIG. 8. Any one of these metabolites may beused in the present invention. The following sentences describe acombination of dehydroaripiprazole with specific mood stabilizers,however it is to be understood that any one of DM-1458, DM-1451,DM-1452, DM-1454 or DCPP, as shown in FIG. 8, could be substituted fordehydroaripiprazole in these disclosed combinations. Dehydroaripiprazole(also called OPC-14857 in FIG. 8) is a preferred metabolite ofaripiprazole. As to the combination of dehydroaripiprazole with one ormore mood stabilizers, the following are non-limiting examples of suchcombinations: dehydroaripiprazole/lithium, dehydroaripiprazole/valproicacid, dehydroaripiprazole/divalproex sodium,dehydroaripiprazole/carbamazapine, dehydroaripiprazole/oxcarbamazapine,dehydroaripiprazole/zonisamide, dehydroaripiprazole/lamotragine,dehydroaripiprazole/topiramate, dehydroaripiprazole/gabapentin,dehydroaripiprazole/levetiracetam and dehydroaripiprazole/clonazepam.Among these combinations, the following are particularly preferable:dehydroaripiprazole/carbamazapine, dehydroaripiprazole/oxcarbamazapine,dehydroaripiprazole/zonisamide, dehydroaripiprazole/lamotragine,dehydroaripiprazole/topiramate, dehydroaripiprazole/gabapentin,dehydroaripiprazole/levetiracetam and dehydroaripiprazole/clonazepam.The pharmaceutical composition comprising the above preferablecombination possesses excellent efficacy. Therefore such composition hasfewer side-effects and an excellent safety profile.

Method of Treating a Mood Disorder, Especially Bipolar Disorder or Mania

Patients with mood disorders may be treated with the compositions of thepresent invention. Such mood disorders include but are riot limited tobipolar disorder, bipolar disorder I, bipolar disorder II, bipolardisorder with and without psychotic features, mania, acute mania,bipolar depression or mixed episodes. Preferred disorders treated withthe method and compositions of the present invention are bipolardisorder and mania. Treatment comprises administration of thecompositions of the present invention to a patient with a mood disordersuch as bipolar disorder or mania, with or without psychotic features,in an amount and dose regimen effective to treat the mood disorder. Thepresent invention includes treatment of mood disorders wherein both thecarbostyril derivative with the previously stated activity and the moodstabilizer are combined together with a pharmaceutically acceptablecarrier in a composition. The present invention further includestreatment of mood disorders wherein both the carbostyril derivative withthe previously stated activity is combined with a pharmaceuticallyacceptable carrier in one composition, the mood stabilizer is combinedwith a pharmaceutically acceptable carrier in a second composition, andthe two compositions are administered at the same or different times toprovide the desired treatment.

Dosage

Dosage of the drug used in the present invention is decided byconsidering the properties of each constituting drug to be combined, theproperties of drugs after combination and symptoms of the patient. Asstated above, the carbostyril derivatives and mood stabilizers may beadministered separately and not combined in one composition. Generaloutlines of the dosage are provided in the following guidelines.

Aripiprazole or a metabolite, such as dehydroaripiprazole, DM-1458,DM-1451, DM-1452, DM-1454 or DCPP: generally about 0.1 to about 100mg/once a day (or about 0.05 to about 50 mg/twice a day), preferablyabout 1 to about 30 mg/once a day (or about 0.5 to about 15 mg/twice aday).

The aripiprazole, or metabolite thereof, may be combined with at leastone of any of the following mood stabilizers at the dose rangesindicated, or administered separately:

Lithium: generally about 300 to about 2400 mg/day, 300 mg to 1200 mgtwice per day, preferably until the plasma lithium concentration isabout 0.8-1.2 mmol/L.

Valproic acid: generally about 750 mg to 2000 mg/day, or 10 to 20mg/kg/day.

Divalproex sodium: generally about 500 to 2500 mg/day.

Carbamazepine: generally about 100 to 3000 mg/day, preferably untilplasma levels reach between about 6.0 to 9.0 mg/L.

Oxcarbamazepine: generally about 600 to 2100 mg/day.

Zonisamide; generally about 100 to 500 mg/day.

Lamotragine: generally about 50 to 500 mg/day, preferably 100 to 400mg/day.

Topiramate: generally, about 25 to about 500 mg/day.

Gabapentin: generally, about 600 to 2400 mg/once a day.

Levetiracetam: generally, about 250 to about 3000 mg/day.

Clonazepam: generally, about 0.1 to 60 mg/day.

Generally, the weight ratio of the first ingredient to the secondingredient is selected in accordance with the above-mentioned guideline.As to the ratio of the first ingredient and the second ingredient, ifthe first ingredient is about 1 part by weight of the former, the secondingredient is used at about 0.01 to about 500 parts by weight,preferably about 0.1 to about 100 parts by weight.

Pharmaceutically Acceptable Carriers

Pharmaceutically acceptable carriers include diluents and excipientsgenerally used in pharmaceutical-preparations, such as fillers,extenders, binders, moisturizers, disintegrators, surfactant, andlubricants.

The pharmaceutical composition of the present invention may beformulated as an ordinary pharmaceutical preparation, for example in theform of tablets, flash melt tablets, pills, powder, liquid, suspension,emulsion, granules, capsules, suppositories or infection (liquid,suspension, etc.), troches, intranasal spray percutaneous patch and thelike.

In case of shaping to tablet formulation, a wide variety of carriersthat are known in this field can be used. Examples include lactose,saccharose, sodium chloride, glucose, urea, starch, xylitol, mannitol,erythritol, sorbitol, calcium carbonate, kaolin, crystalline cellulose,silic acid and other excipients; water, ethanol, propanol, simple syrup,glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dried starch, sodium alginate, agarpowder, laminaran powder, sodium hydrogencarbonate, calcium carbonate,polyoxyethylene sorbitan fatty acid esters. sodium lauryl sulfate,stearic acid monoglyceride, starch, lactose and other disintegrators;white sugar, stearin, cacao butter, hydrogenated oil and otherdisintegration inhibitors; quaternary ammonium salt, sodium laurylsulfate and other absorption accelerator; glycerine, starch and othermoisture retainers; starch, lactose, kaolin, bentonite, colloidal silicacid and other adsorbents; and refined talc, stearate, boric acidpowder, polyethylene glycol and other lubricants and the like. Tabletscan also be formulated if necessary as tablets with ordinary coatings,such as sugar-coated tablets, gelatin-coated tablets, enteric coatedtablets and film coated tablets, as well as double tablets andmultilayered tablets.

In case of shaping to pills, a wide variety of carriers that are knownin this field can be used. Examples include glucose, lactose, starch,cacao butter, hardened vegetable oil, kaolin, talc and other excipients;gum arable powder, traganth powder, gelatin, ethanol and other binders;and laminaran, agar and other disintegrators and the like.

In case of shaping to a suppository formulation, a wide variety ofcarriers that are known in the field can be used. Examples includepolyethylene glycol, cacao butter, higher alcohol, esters of higheralcohol, gelatin semi-synthetic glyceride and the like.

Capsules are prepared according to ordinary methods by mixingaripiprazole anhydride crystals as the first ingredient and the secondingredient, and the various carriers described above and packing them inhard gelatin capsules, soft capsules hydroxypropylmethyl cellulosecapsules (HPMC capsules) and the like.

In addition, colorants, preservatives, perfumes, flavorings, sweetenersand the like as well as other drugs may be contained in thepharmaceutical composition.

The amounts of the first ingredient and the second ingredient to becontained in the pharmaceutical composition of the present invention aresuitably selected from a wide range depending on the diseases to betreated. Generally, about 1 to 70 parts by weight, preferably about 1 to30 parts by weight of the first ingredient and the second ingredient arecombined in the total amount on the basis of the pharmaceuticalcomposition.

The methods for administration of the pharmaceutical composition of thepresent invention are not specifically restricted. The composition isadministered depending on each type of preparation form, and the age,gender and other condition of the patient (degree and conditions of thedisease, etc.). For example, tablets, pills, liquids, suspensions,emulsions, granules and capsules are administered orally. In case ofinjection preparation, it is administered intravenously either singly ormixed with a common auxiliary liquid such as solutions of glucose oramino acid. Further, if necessary, the injection preparation is singlyadministered intradermally, subcutaneously or intraperitoneally. In caseof a suppository, it is administered intrarectally.

Administration forms of the pharmaceutical composition of the presentinvention may be any type by which the effective levels of botharipiprazole and mood stabilizers can be provided in vivo at the sametime. In one embodiment, aripiprazole together with a mood stabilizerare contained in one pharmaceutical composition and this composition maybe administered. On the other hand, each one of aripiprazole and a moodstabilizer are contained individually in a pharmaceutical preparationrespectively, and each one of these preparations may be administered atthe same or at different times.

Dosage of the pharmaceutical composition of the present invention fortreating and improving mood disorders may be used relatively in a smallamount, because the composition possesses excellent efficacy. Thereforethe composition has fewer side-effects and an excellent safety profile.

The pharmaceutical composition of the present invention can be manifestin a wide range of neurotransmission accommodation actions. As a result,the composition of the present invention establishes pseudo-homeostaticdopaminergic and serotoninergic neurotransmission (as a result ofpartial agonism), which, as a result of neuropathophysiologicalprocesses has ceased to function normally. The mood disorders which canbe treated by the pharmaceutical composition of the present inventionincludes the mood disorders classified in “Diagnostic and StatisticalManual of Mental Disorders” Fourth Edition (DSM-IV) published by theAmerican Psychiatric Association. These mood disorders include, forexample, bipolar disorder such as bipolar disorder I or II, bipolardisorder with or without psychotic features, mania, acute mania, bipolardepression or mixed episodes.

In addition, the pharmaceutical composition of the present invention iseffective on schizophrenia and other psychotic disorders. Thesedisorders include, for example, depressive disorders such as majordepressive disorder, endogenous depression, melancholia, depression incombination with psychotic episodes, refractory depression, dementia ofthe Alzheimer's disease with depressive symptoms, Parkinson's diseasewith depressive symptoms, senile dementia, mood disorder associated withcerebral blood vessels, mood disorder following head injury and thelike; anxiety disorders such as panic disorder, obsessive-compulsivedisorder, generalized anxiety disorder, posttraumatic stress disorder,social phobia, specific phobia and the like; eating disorders; sleepdisorders; adjustment disorders; personality disorders; mentalretardations; learning disorders; pervasive developmental disorders;attention-deficit and disruptive behavior disorders; tic disorders;delirium; dementia; amnestic disorders; other cognitive disorders;alcohol-related disorders; amphetamine-related disorders;cocaine-related disorders; nicotine-related disorders; sedative-,hypnotic-, or anxiolytic-related disorders; sexual and gender identitydisorders. These disorders are classified in “Diagnostic and StatisticalManual of Mental Disorders” Fourth Edition (DSM-IV) published by theAmerican Psychiatric Association.

The present invention will be explained more in detail by illustratingReference Examples, Example and Formulation Sample Examples. First,analytical methods are explained.

Analytical Methods

(1) The ¹H-NMR Spectrum was Measured in DMSO-d₆ by Using TMS as theStandard

(2) Powder X-Ray Diffraction

By using RAD-2B diffraction meter manufactured by Rigaku Denki, thepowder x-ray diffraction pattern was measured at room temperature byusing a Cu Ka filled tube (35 kV 20 mA) as the x-ray source with awide-angle goniometer, a 1° scattering slit, an 0.15 mmlight-intercepting slit, a graphite secondary monochromator and ascintillation counter. Data collection was done in 2θ continuous scanmode at a scan speed of 5+/minute in scan steps of 0.02° in the range of3° to 40°.

(3) The IR Spectrum was Measured by the KBr Method

(4) Thermogravimetric/Differential Thermal Analysis

Thermogravimetric/differential thermal analysis was measured by usingSSC 5200 control unit and TG/DTA 220 simultaneous differentialthermal/thermogravimetric measuring unit manufactured by Seiko Corp.Samples (5-10 mg) were placed in open aluminum pans and heated at from20° C. to 200° C. in a dry nitrogen atmosphere at a heating rate of 5°C./minute. α-Alumina was used as the standard substance.

(5) Differential Scanning Calorimetry

Thermogravimetric/differential thermal analysis was measured by usingSSC 5200 control unit and DSC 220C differential scanning calorimetermanufactured by Seiko Corp. Samples (5-10 mg) were placed in crimpedaluminum pans and heated from 20° C. to 200° C. in a dry nitrogenatmosphere at a heating rate of 5° C./minute. α-Alumina was used as thestandard substance.

(6) Particle Size Measurement

The particles (0.1 g) to be measured were suspended in a 20 ml n-hexanesolution of 0.5 g soy lecithin, and particle size was manufactured byusing a size distribution measuring meter (Microtrack HRA, manufacturedby Microtrack Co.).

Reference Example 1

7-(4-Chlorobutoxy)-3,4-dihydrocarbostyril (19.4 g) and monohydrochloride16.2 g of 1-(2,3-dichlorophenyl) piperadine 1 hydrochloride were addedto a solution of 8.39 g of potassium carbonate dissolved in 140 ml ofwater, and refluxed for 3 hours under agitation. After the reaction wascomplete, the mixture was cooled and the precipitated crystals collectedby filtration. These crystals were dissolved in 350 ml of ethyl acetate,and about 210 ml of water/ethyl acetate azeotrope was removed underreflux. The remaining solution was cooled, and the precipitated crystalswere collected by filtration. The resulting crystals were dried at 60°C. for 14 hours to obtain 20.4 g (74.2%) of crude product ofaripiprazole.

The crude product of aripiprazole (30 g) obtained above wasre-crystallized from 450 ml of ethanol according to the methodsdescribed in Japanese Unexamined Patent Publication No. 191256/1990, andthe resulting crystals were dried at 80° C. for 40 hours to obtainaripiprazole anhydride crystals. The yield was 29.4 g (98.0%).

The melting point (mp) of these aripiprazole anhydride crystals was 140°C., which is identical to the melting point of the aripiprazoleanhydride crystals described in Japanese Unexamined Patent PublicationNo. 191256/1990.

Reference Example 2

The crude product of aripiprazole (6930 g) obtained in Reference Example1 was heat dissolved by heating in 138 liters of hydrous ethanol (watercontent 20% by volume) according to the method presented at the 4thJoint Japanese-Korean Symposium on Separation Technology, the solutionwas gradually (2-3 hours) cooled to room temperature, and then waschilled to near 0° C. The precipitated crystals were collected byfiltration, about 7200 g of aripiprazole hydrate (wet-state).

The wet-state aripiprazole hydrate crystals obtained above were dried at80° C. for 30 hours to obtain 6480 g (93.5%) of aripiprazole hydratecrystals. The melting point (mp) of these crystals was 139.5° C.

The water content of the crystals were confirmed by the Karl Fischermethod, the moisture value was 0.03%, thus the crystals were confirmedas anhydrous product.

Reference Example 3

The aripiprazole hydrate (820 g) in wet state obtained from ReferenceExample 2 was dried at 50° C. for 2 hours to obtain 780 g ofaripiprazole hydrate crystals. The moisture value of the crystals had amoisture value was 3.82% measured according to the Karl Fischer method.As shown in FIG. 6, thermogravimetric/differential thermal analysisrevealed endothermic peaks at 75.0, 123.5 and 140.5° C. Becausedehydration began near at 70° C., there was no clear melting point (rap)was observed.

As shown in FIG. 7, the powder x-ray diffraction spectrum ofaripiprazole hydrate obtained by this method exhibited characteristicpeaks at 2θ=12.6°, 15.1°, 17.4°, 18.2°, 18.7°, 24.8° and 27.5°.

The powder x-ray diffraction spectrum of this aripiprazole hydrate wasidentical to the powder x-ray diffraction spectrum of aripiprazolehydrate presented at the 4th Joint Japanese-Korean Symposium onIsolation Technology.

Reference Example 4

The aripiprazole hydrate crystals (500.3 g) obtained in ReferenceExample 3 were milled by using a sample mill (small size atomizer). Themain axis rotation rate was set to 12,000 rpm and the feed rotation rateto 17 rpm, and a 1.0 mm herringbone screen was used. Milling wasfinished in 3 minutes, and obtained 474.6 g (94.9%) of aripiprazolehydrate A.

The aripiprazole hydrate A (powder) obtained in this way had a meanparticle size of 20-25 μm. The melting point (mp) was undeterminedbecause dehydration was observed beginning near at 70° C.

The aripiprazole hydrate A (powder) obtained above exhibited an ¹H-NMR(DMSO-d₆, TMS) spectrum which was substantially identical to the ¹H-NMRspectrum shown in FIG. 2. Specifically, it had characteristic peaks at1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H),2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt,J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H),6.49 ppm (dd, J−8.4 Hz, J−2.4 Hz, 1H), 7.04 ppm (d, J−8.1 Hz, 1H),7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

The aripiprazole hydrate A (powder) obtained above had a powder x-raydiffraction spectrum which was substantially identical to the powderx-ray diffraction spectrum shown in FIG. 3. specifically, it hadcharacteristic peaks at 2θ=12.6°, 15.4°, 17.3°, 18.0°, 18.6°, 22.5° and24.8°. This pattern is different from the powder x-ray spectrum ofunmilled Aripiprazole hydrate shown in FIG. 7.

The aripiprazole hydrate A (powder) obtained above had infraredabsorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and784 cm³¹ ¹ on the IR (KBr) spectrum.

As shown in FIG. 1, the aripiprazole hydrate A (powder) obtained abovehad a weak peak at 71.3° C. in thermogravimetric/differential thermalanalysis and a broad endothermic peak (weight loss observedcorresponding to one molecule of water) between 60-120° C. which wasclearly different from the endothermic curve of unmilled aripiprazolehydrate (see FIG. 6).

It will be appreciated that other embodiments and uses will be apparentto those skilled in the art and that the invention is not limited tothese specific illustrative examples.

Example 1

The aripiprazole hydrate A (powder) (44.29 kg) obtained in the ReferenceExamples was dried at 100° C. for 24 hours by using a hot air dryer andfurther heated at 120° C. for 3 hours, to obtain 42.46 kg (yield; 99.3%)of aripiprazole anhydride Crystals B. These aripiprazole anhydridecrystals B had a melting point (mp) of 139.7° C.

The aripiprazole anhydride crystals B obtained above had an spectrum(DMSO-d₆, TMS) which was substantially identical to the ¹H-NMR spectrumshown in FIG. 4. Specifically, they had characteristic peaks at1.55-1.63 ppm (m, 2H), 1.60-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H),2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt,J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H),6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

The aripiprazole anhydride crystals B obtained above had a powder x-raydiffraction spectrum which was substantially the identical to the powderx-ray diffraction spectrum shown in FIG. 5, Specifically, they hadcharacteristic peaks at 2θ=11.0°, 16.6°, 19.3°, 20.3° and 22.1°.

The aripiprazole anhydride crystals B obtained above had remarkableinfrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173,960 and 779 cm⁻¹ on the IR (KBr) spectrum. The aripiprazole anhydridecrystals B obtained above exhibited an endothermic peak near about at141.5° C. in thermogravimetric/differential thermal analysis. Thearipiprazole anhydride crystals B obtained above exhibited anendothermic peak near about at 140.7° C. in differential scanningcalorimetry.

Example 2

Receptor Binding at the 5HT_(1A) Receptor

1. Materials and Methods 1.1 Test Compound

7-(4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]-butoxy-3,4-dihydrocarbostyril(aripiprazole) was used as test compound.

1.2 Reference Compounds

Serotonin (5-HT) and WAY-100635(N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)-cyclohexanecarboxamide,a 5-HT_(1A) receptor antagonist, manufactured by RBI (Natick, Mass.)were used as reference compounds.

1.3 Vehicle

Dimethyl sulfoxide (DMSO) manufactured by Sigma Chemical Co. (St. Louis,Mo.) was used as vehicle.

1.4 Preparation of Test and Reference Compounds

Test compound was dissolved in 100% dimethyl sulfoxide (DMSO) to yield100 μM stock solutions (final concentration of DMSO in all tubescontaining test compound was 1%, v/v). All other reference compoundswere prepared by the same method using double-distilled water ratherthan DMSO.

1.5 Experimental Procedure for the [³⁵S]GTPγS Binding Assay

Test and reference compounds were studied in triplicate at 10 differentconcentrations (0.01, 0.1, 1, 5, 10, 50, 100, 1000, 10000 and 50000 nM)for their effects upon basal [³⁵S]GTPγS binding to h5-HT_(1A) CHO cellmembranes. Reactions were performed in 5 ml glass test tubes containing8 μl of test/reference drug mixed with 792 μl of buffer (25 mM Tris HCl,50 mM NaCl, 5 mM MgCl₂, 0.1 mM EGTA, pH-7.4) containing GDP (1 μM),[³⁵S]GTPS (0.1 nM) and h5-HT_(1A) CHO cell membranes (10 μgprotein/reaction; NSN Life Science Products, Boston, Mass.; catalog,CRM035, lot #501-60024, GenBank #X13556). Reactions proceeded for 60 minat room temperature and were terminated by rapid filtration throughWhatman GF/B filter paper, using a Brandel harvester and 4×3 ml ice-coldbuffer washes. S radioactivity bound to the filter paper was measuredusing liquid scintillation counting (1272 Clinigamma, LKB/Wallach).

1.6 Experimental Procedure to Determine the Binding Affinity of the Testcompound Aripiprazole at the h5-HT_(1A) Receptor

Test compound was studied in triplicate at 10 different concentrations(0.01, 0.1, 1, 10, 50,100, 500, 1000, 5000 and 10000 nM) to determineits displacement of [³H]8-OH-DPAT (1 nM; NEN Life Sciences; catalog #NET929, lot #3406035, Specific Activity=124.9 Ci/mmol) binding toh5-HT_(1A) receptors in CHO cell membranes (15-20 μg protein; NEN LifeScience Products, catalog #CRM035, lot #501-60024). Membranes (396 μl)were incubated in 5 ml glass tubes containing [³H]8-OH-DPAT (396 μl),test compound or vehicle (8 μl) and buffer A (50 mM Tris.HCl, 10 mMHgSO₄, 0.5 mM EDTA, 0.1% (w/v) ascorbic acid, pH=7.4). All assaysproceeded for 60 min at room temperature and were terminated by rapidfiltration through Whatman GF/B filter paper (presoaked in buffer B; 50mM Tris.HCl, pH=7.4), using a Brandel harvester and 4×1 ml ice-coldwashes with buffer B. Non-specific binding was determined in thepresence of 10 μM (+)8-OH-DPAT.

1.7 Parameters Determined

Serotonin (5-HT) is a full 5-HT_(1A) receptor agonist which stimulatesincreases in basal [³⁵S]GTPγS binding to h5-HT_(1A) receptors inrecombinant CHO cell membranes. The test compound was studied at 10concentrations to determine effects upon basal [³⁵S]GTPγS bindingrelative to that produced by 10 μM 5-HT. The relative potency (EC₅₀, 95%confidence interval) and intrinsic agonist activity (% of E_(max) for 10μM 5-HT) was calculated for each compound by computerized non-linearregression analysis of complete concentration-effect data. The bindingaffinity of test compound at the h5-HT_(1A) receptor was determined byits ability to prevent [³H]8-OH-DPAT binding to CHO cell membranes thatexpress this receptor. Non-linear regression analysis of the competitionbinding data was used to calculate an inhibition constant (IC₅₀, 95%confidence interval), which is the concentration of test compound thatoccupies half of the h5-HT_(1A) sites specifically bound by[³H]8-OH-DPAT. The affinity of h5-HT_(1A) receptors for test compound(Ki, 35% confidence interval) was calculated by the equation,Ki=(IC₅₀)/(1+([[³H]8-OH-DPAT]/Kd), where the Kd for [³H]8-OH-DPAT ath5-HT_(1A)=0.69 nM (NEN Life Sciences). All estimates of drug bindingaffinity, potency and intrinsic efficacy at the h5-HT_(1A) receptor werecalculated using GraphPad Prism version 3.00 for Windows (GraphPadSoftware, San Diego, Calif.).

2. Results

The test compound and 5-HT produced concentration-dependent increasesabove basal [³⁵S]GTPγS binding. 1% DMSO tested alone had no effect uponbasal or drug-induced [³⁵S]GTPγS binding.

The test compound (EC₅₀→2.12 nM), 5-HT (EC₅₀=3.67 nM), potentlystimulated basal [³⁵S]GTPγS binding. Potency and intrinsic agonistefficacy estimates were derived by non-linear regression analysis withcorrelation coefficients (r²)>0.93 in each case (Table 1). The testcompound exerted partial agonist efficacies in the 65-70% range.WAY-100635 produced no significant change (unpaired Student's t-test) inbasal [³⁵S]GTPγS 5 binding at all concentrations tested (Table 1).WAY-100635 did, however, completely inhibit the effects of 5-HT and testcompound upon [³⁵S]GTPγS binding to h5-HT_(1A) receptors in CHO ceilmembranes (Table 2). Tables 1 and 2 are shown below. The test compounddemonstrated high affinity binding to h5-HT_(1A) receptors in CHO cellmembranes (IC₅₀4.03 nM, 95% confidence interval=2.67 to 6.08 nM; Ki=1.65nM, 95% confidence interval=1.09 to 2.48.

TABLE 1 Potenct (EC₅₀) and Intrinsic Agonist Efficacy (E_(max)) of Testcompound and Reference Drugs in a h5-HT_(1A) [³⁵S] GTPγS CHO-cellMembrane Binding Assay. EC₅₀, nM (95% Goodness Confidence E_(max) of FitDrug Interval (% ± SEM) (r²) Test 2.12 (0.87 to 5.16) 68.13 ± 3.16 0.986Compound 5-HT 3.67 (1.56 to 8.63) 98.35 ± 4.47 0.986 WAY-100635 ---------- -----

TABLE 2 Inhibitory Potency (IC₅₀) of WAT-100635 versus 1 μMConcentration of 5-HT and Test compound in a h5-HT_(1A) [³⁵S] GTPγSCHO-cell Membrane Binding Assay. WAY-100635 Inhibition Goodnees DrugPotency, IC₅₀, nM of Fit Combination (95% Confidence Interval) (r²)5-HT + 217.1 0.988 WAY-100635 (127.4 to 369.7) Test Compound + 392.20.989 WAY-100635 (224.1 to 686.2)

Example 3 Formulation Examples

Several non-limiting formulation examples aripiprazole ordehydroaripiprazole with mood stabilizers are presented below.

Formulation Sample Example 1

Formulation Sample Example 1 Aripiprazole Anhydride Crystals B  5 mgLithium 600 mg Starch 131 mg Magnesium stearate  4 mg Lactose  50 mgTotal 800 mg

According to a preparation method which is well-known to a person havingan ordinary skill in the art, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 2

Formulation Sample Example 2 Aripiprazole Anhydride Crystals B   5 mgValproic Acid 1000 mg Starch  131 mg Magnesium stearate   4 mg Lactose 60 mg Total 1200 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 3

Formulation Sample Example 3 Aripiprazole Anhydride Crystals B  5 mgDivalproex sodium 750 mg Starch 131 mg Magnesium stearate  4 mg Lactose 60 mg Total 950 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 4

Formulation Sample Example 4 Aripiprazole Anhydride Crystals B  5 mgCarbamazepine 500 mg Starch 131 mg Magnesium stearate  4 mg Lactose  60mg Total 700 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 5

Formulation Sample Example 5 Aripiprazole Anhydride Crystals B   5 mgOxcarbamazepine  800 mg Starch  131 mg Magnosium stearate   4 mg Lactose 60 mg Total 1000 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 6

Formulation Sample Example 6 Aripiprazole Anhydride Crystals B  5 mgZonisamide 300 mg Starch 131 mg Magnesium stearate  4 mg Lactose  60 mgTotal 500 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 7

Formulation Sample Example 7 Aripiprazole Anhydride Crystals B  5 mgLamotragine 250 mg Starch 131 mg Magnesium stearate  4 mg Lactose  60 mgTotal 450 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 8

Aripiprazole Anhydride Crystals B 5 mg Topiramate 250 mg Starch 131 mgMagnesium stearate 4 mg Lactose 60 mg Total 450 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 9

Aripiprazole Anhydride Crystals B 5 mg Gabapentin 800 mg Starch 131 mgMagnesium stearate 4 mg Lactose 60 mg Total 1000 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 10

Aripiprazole Anhydride Crystals B 5 mg Levetiracetam 600 mg Starch 131mg Magnesium stearate 4 mg Lactose 60 mg Total 800 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Several non-limiting formulation examples of dehydroaripiprazole andmood stabilizers are presented below. It is to be understood that anyone of DM-1458 DM-1451, DM-1452, DM-1454 or DCPP, as shown in FIG. 8,could be substituted for dehydroaripiprazole in these disclosedformulations.

Formulation Sample Example 11

Dehydroaripiprazole 5 mg Lithium 600 mg Starch 131 mg Magnesium stearate4 mg Lactose 60 mg Total 800 mg

According to a preparation method which is well-known to a person havingan ordinary skill in the art, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 12

Dehydroaripiprazole 5 mg Valproic Acid 1000 mg Starch 131 mg Magnesiumstearate 4 mg Lactose 60 mg Total 1200 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 13

Dehydroaripiprazole 5 mg Divalproex sodium 750 mg Starch 131 mgMagnesium stearate 4 mg Lactose 60 mg Total 950 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 14

Dehydroaripiprazole 5 mg Carbamazepine 500 mg Starch 131 mg Magnesiumstearate 4 mg Lactose 60 mg Total 700 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 15

Dehydroaripiprazole 5 mg Oxcarbamazepine 800 mg Starch 131 mg Magnesiumstearate 4 mg Lactose 60 mg Total 1000 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 16

Dehydroaripiprazole 5 mg Zonisamide 300 mg Starch 131 mg Magnesiumstearate 4 mg Lactose 60 mg Total 500 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 17

Dehydroaripiprazole 5 mg Lamotragine 250 mg Starch 131 mg Magnesiumstearate 4 mg Lactose 60 mg Total 450 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 18

Dehydroaripiprazole 5 mg Topiramate 250 mg Starch 131 mg Magnesiumstearate 4 mg Lactose 60 mg Total 450 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 19

Dehydroaripiprazole 5 mg Gebapentin 800 mg Starch 131 mg Magnesiumstearate 4 mg Lactose 60 mg Total 1000 mg

According to a common method, the tablet containing the above mentionedso Emulation is prepared.

Formulation Sample Example 20

Dehydroaripiprazole 5 mg Levetiracetam 600 mg Starch 131 mg Magnesiumstearate 4 mg Lactose 60 mg Total 800 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 21

Aripiprazole Anhydride Crystals B 5 mg clonazepam 600 mg Starch 131 mgMagnesium stearate 4 mg Lactose 60 mg Total 800 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Formulation Sample Example 22

Dehydroaripiprazole 5 mg clonazepam 600 mg Starch 131 mg Magnesiumstearate 4 mg Lactose 60 mg Total 800 mg

According to a common method, the tablet containing the above mentionedformulation is prepared.

Example 4

Method of Treatment of Patients with a New Diagnosis, Recurrent orRefractory Episode of Bipolar Disorder (I or II) with or withoutpsychotic features, manic or mixed episode as defined by DSM-IV-Rcriteria.

A combination of aripiprazole, or an aripiprazole metabolite, and atleast one mood stabilizer is evaluated as a therapy for patients with anew diagnosis, recurrent or refractory episode of bipolar disorder (I orII), acute mania, or bipolar depression. Patients ranging in age from 18to 65 years who are diagnosed with bipolar disorder (I or II), acutemania, or bipolar depression are evaluated to ensure that they have abaseline Young Mania Rating Scale (YMRS) score of greater than 24. Onlypatients with this YMRS score receive treatment. These patients areinterviewed to obtain a complete medical and psychiatric history.Aripiprazole, or an aripiprazole metabolite, is first administered at adose of 10 mg/day and increased to 30 mg/day as needed in the opinion ofthe monitoring psychiatrist. Aripiprazole, or an aripiprazolemetabolite, is administered to these patients at a dose of from 10mg/day to 30 mg/day for a period of at least four weeks, and up to eightweeks for patients who respond well to this treatment during the firstfour weeks. The aripiprazole, or the aripiprazole metabolite, isadministered together with at least one mood stabilizer, wherein themood stabilizer is lithium, valproic acid, divalproex sodium,carbamazapine, oxcarbamazapine, zonisamide, lamotragine, topiramate,gabapentin, levetiracetam or clonazepam.

The aripiprazole, or the aripiprazole metabolite, can be administered inone dosage form, for example a tablet, and the mood stabilizer may beadministered in a separate dosage form, for example a tablet. Theadministration may occur at about the same time or at different timesduring the day. Dosages may be within the ranges provided above for eachof aripiprazole, an aripiprazole metabolite and for the mood stabilizer.

Alternatively, a dosage form containing aripiprazole, or an aripiprazolemetabolite, in administered in combination with at least one moodstabilizer and a pharmaceutically acceptable carrier. Such combinationsinclude without limitation the following: aripiprazole/lithium,aripiprazole/valproic acid, aripiprazole/divalproex sodium,aripiprazole/carbamazapine, aripiprazole/oxcarbamazapine,aripiprazole/zonisamide, aripiprazole/lamotragine,aripiprazole/topiramate, aripiprazole/gabapentin,aripiprazole/levetiracetam and aripiprazole/clonazepam. An improvementin alleviation of symptoms of bipolar disorder (I or II), acute mania,or bipolar depression is observed in these patients followingadministration of aripiprazole, or aripiprazole metabolite, and the oneor more mood stabilizers, as shown by results of testing performedduring and after the duration of administration of aripiprazole, or anaripiprazole metabolite, and the mood stabilizer. The YMRS and othermeasures such as CGI, AIMS, SAS, Simpson & Angus and Barnes, commonlyknown to one of ordinary skill in the art, are administered to thesepatients. Results demonstrate a normalization of mood.

Example 5

Efficacy of Aripiprazole in combination with valproate or lithium in thetreatment of mania in patients partially nonresponsive to valproate orlithium monotherapy.

A 6-week double-blind, randomized, placebo-controlled trial is conductedto determine the efficacy of combined therapy with aripiprazole andeither valproate or lithium compared with valproate or lithium alone intreating acute manic or mixed bipolar episodes. The methods used aregenerally as described in Tohen et al., (Arch. Gen. Psychiatry, 2002January;59 (1):62-9). The objective is to evaluate the efficacy ofaripiprazole (1-30 mg/day) vs placebo when added to ongoingmood-stabilizer therapy as measured by reductions in Young Mania RatingScale (YMRS) scores. Patients with bipolar disorder, manic or mixedepisode, who are inadequately responsive to more than 2 weeks of lithium(600 mg/day) or valproate (500 mg/day) therapy, are randomized toreceive cotherapy (aripiprazole+mood-stabilizer) or monotherapy(placebo+mood-stabilizer). The results indicate that aripiprazolecotherapy improves patients' YMRS total scores more than monotherapy.Clinical response rates (× or =50% improvement on YMRS) are higher withcotherapy. Aripiprazole cotherapy improves 21-item Hamilton DepressionRating Scale (HAMD-21) total scores more than monotherapy. In patientswith mixed-episodes with moderate to severe depressive symptoms (DSM-XVmixed episode; HAMD-21 score of > or =20 at baseline), aripiprazolecotherapy improves HAMD-21 scores compared to monotherapy.Extrapyramidal symptoms (Sirapson-Angus Scale, Barnes Akathisia Scale,Abnormal Involuntary Movement Scale) are not significantly changed frombaseline to end point in either treatment group. Compared with the useof valproate or lithium alone, the addition of aripiprazole providedsuperior efficacy in the treatment of manic and mixed bipolar episodes.

Example 6

Efficacy of Dehydroaripiprazole in combination with valproate or lithiumin the treatment of mania in patients partially nonresponsive tovalproate or lithium monotherapy.

A 6-week double-blind, randomized, placebo-controlled trial is conductedto determine the efficacy of combined therapy with dehydroaripiprazoleand either valproate or lithium, compared with valproate or lithiumalone, in treating acute manic or mixed bipolar episodes. The methodsused are generally as described in Tohen et al., (Arch. Gen. Psychiatry,2002 January;59(1);62-9). The objective is to evaluate the efficacy ofdehydroaripiprazole (1-30 mg/day) vs placebo when added to ongoingmood-stabilizer therapy as measured fay reductions in Young Mania RatingScale (YMRS) scores. Patients with bipolar disorder, manic- or mixedepisode, who are inadequately responsive to more than 2 weeks of lithium(600 mg/day) or valproate (500 mg/day) therapy, are randomized toreceive cotherapy (dehydroaripiprazole+mood-stabilizer) or monotherapy(placebo+mood-stabilizer). The results indicate that dehydroaripiprazolecotherapy improves patients' YMRS total scores more than monotherapy.Clinical response rates (> or =50% improvement on YMRS) are higher withcotherapy. Dehydroaripiprazole cotherapy improves 21-item HamiltonDepression Rating Scale (HAMD-21) total scores more than monotherapy. Inpatients with mixed-episodes with moderate to severe depressive symptoms(DSM-IV mixed episode; HAMD-21 score of > or =20 at baseline),dehydroaripiprazole cotherapy improves HAMD-21 scores compared tomonotherapy. Extrapyramidal symptoms (Simpson-Angus Scale, BarnesAkathisia Scale, Abnormal Involuntary Movement Scale) are notsignificantly changed from baseline to end point in either treatmentgroup. Compared with the use of valproate or lithium alone, the additionof dehydroaripiprazole provided superior efficacy in the treatment ofmanic arid mixed bipolar episodes.

Example 7

A double-blind, randomized, placebo-controlled study of Aripiprazole asadjunctive treatment for adolescent mania.

This randomized/double-blind, placebo-controlled study examines theefficacy and tolerability of aripiprazole in combination with divalproex(DVP) for acute mania in adolescents with bipolar disorder. The methodsemployed are essentially as described by Delbello et al., (J. Am. Acad.Child Adolesc. Psychiatry, 2002 October;41(10):1216-23). It ishypothesized that DVP in combination with aripiprazole is more effectivethan DVP alone for treating mania associated with adolescent bipolardisorder. Thirty manic or mixed bipolar I adolescents (12-18 years)receive an initial DVP dose of 20 mg/kg and are randomly assigned to 6weeks of combination therapy with aripiprazole/about 10 mg/day orplacebo. Primary efficacy measures are change from baseline to endpointin Young Mania Rating Scale (YMRS) score and YMRS response rate. Safetyand tolerability are assessed weekly. The DVP+aripiprazole groupdemonstrates a greater reduction in YMRS score's from baseline toendpoint than the DVP+placebo group. Moreover, YMRS response rate issignificantly greater in the DVP+aripiprazole group than in theDVP+placebo group. No significant group differences from baseline toendpoint in safety measures are noted. Sedation, rated as mild ormoderate, is more common in the DVP+aripiprazole group than in theDVP+placebo group. The results indicate that aripiprazole in combinationwith DVP is more effective for the treatment of adolescent bipolar maniathan DVP alone. In addition, the results suggest that aripiprazole iswell tolerated when used in combination with DVP for the treatment ofmania.

Example 8

A double-blind, randomized, placebo-controlled study ofDehydroaripiprazole as adjunctive treatment for adolescent mania.

This randomized, double-blind, placebo-controlled study examines theefficacy and tolerability of dehydroaripiprazole in combination withdivalproex (DVP) for acute mania in adolescents with bipolar disorder.The methods employed are essentially as described by Delbello et al.,(J. Am. Acad. Child Adolesc. Psychiatry, 2002 October;41(10):1216-23).It is hypothesized that DVP in combination with dehydroaripiprazole ismore effective than DVP alone for treating mania associated withadolescent bipolar disorder. Thirty manic or mixed bipolar I adolescents(12-18 years) receive an initial DVP dose of 20 mg/kg and are randomlyassigned to 6 weeks of combination therapy with dehydroaripiprazole,about 10 mg/day or placebo. Primary efficacy measures are change frombaseline to endpoint in Young Mania Rating Scale (YMRS) score and YMRSresponse rate. Safety and tolerability are assessed weekly. TheDVP+dehydroaripiprazole group demonstrates a greater reduction in YMRSscores from baseline to endpoint than the DVP+placebo group. Moreover,YMRS response rate is significantly greater in theDVP+dehydroaripiprazole group than in the DVP+placebo group. Nosignificant group differences from baseline to endpoint in safetymeasures are noted. Sedation, rated as mild or moderate, is more commonin the DVP+dehydroaripiprazole group than in the DVP+placebo group. Theresults indicate that dehydroaripiprazole in combination with DVP ismore effective for the treatment of adolescent bipolar mania than DVPalone. In addition, the results suggest that aripiprazole is welltolerated when used in combination with DVP for the treatment of mania.

All patents, patent applications, scientific and medical publicationsmentioned herein are hereby incorporated in their entirety. It should beunderstood, of course, that the foregoing relates only to preferredembodiments of the present invention and that numerous modifications oralterations may be made therein without departing from the spirit andthe scope of the invention as set forth in the appended claims.

What is claimed is: 1-16. (canceled)
 17. A pharmaceutical compositioncomprising: at least one compound selected from aripiprazole, or ametabolite of aripiprazole selected from the group consisting ofdehydroaripiprazole,2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)-butyl]-piperazin-1-yl}-phenylsulfate (DM-1458),7-{4-[4-(2,3-dichloro-4-hydroxyphenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2-(1H)-quinolinone(DM-1451),7-{4-[4-(2,3-diohlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-4-hydroxy-2-(1H)-quinolinone(DM-1452),1β-(2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)-butyl]-piperazin-1-yl}-phenoxy)-D-glucopyaranuronicacid (DM-1454) and 1-(2,3-dichlorophenyl)piperazine (DCPP) incombination with at least one mood stabilizer selected from the groupconsisting of lithium, valproic acid, divalproex sodium, carbamazapine,oxcarbamazapine, zonisamide, lamotragine, topiramate, gabapentin,levetiracetam, clonazepam, and a salt thereof; and a pharmaceuticallyacceptable carrier.
 18. The composition of claim 17, wherein the atleast one compound is aripiprazole.
 19. The composition of claim 17,wherein the at least one compound is dehydroaripiprazole,2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)-butyl]-piperazin-1-yl}-phenylsulfate (DM-1458),7-{4-[4-(2,3-dichloro-4-hydroxyphenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2-(1H)-quinolinone(DM-1451),7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-4-hydroxy-2-(1H)-quinolinone(DM-1452),1β-(2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)-butyl]-piperazin-1-yl}-phenoxy)-D-glucopyaranuronicacid (DM-1454) or 1-(2,3-dichlorophenyl)piperazine (DCPP).
 20. Thecomposition of claim 18, wherein aripiprazole is anhydrous aripiprazolecrystals B.
 21. A pharmaceutical composition comprising: at least onecompound selected from aripiprazole, or a metabolite of aripiprazoleselected from the group consisting of dehydroaripiprazole,2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)-butyl]-piperazin-1-yl}-phenylsulfate (DM-1458),7-{4-[4-(2,3-dichloro-4-hydroxyphenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2-(1H)-quinolinone(DM-1451),7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-4-hydroxy-2-(1H)-quinolinone(DM-1452),1β-(2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)-butyl]-piperazin-1-yl}-phenoxy)-D-glucopyaranuronicacid (DM-1454) and 1-(2,3-dichlorophenyl)piperazine (DCPP) incombination with at least one mood stabilizer selected from the groupconsisting of lithium, valproic acid, divalproex sodium, and a saltthereof; and a pharmaceutically acceptable carrier.
 22. The compositionof claim 21, wherein the at least one compound is aripiprazole and theat least one mood stabilizer is lithium.
 23. The composition of claim21, wherein the at least one compound is dehydroaripiprazole,2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)-butyl]-piperazin-1-yl}-phenylsulfate (DM-1458),7-{4-[4-(2,3-dichloro-4-hydroxyphenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2-(1H)-quinolinone(DM-1451),7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-4-hydroxy-2-(1H)-quinolinone(DM-1452),1β-(2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)-butyl]-piperazin-1-yl}-phenoxy)-D-glucopyaranuronicacid (DM-1454) or 1-(2,3-dichlorophenyl)piperazine (DCPP) and the atleast one mood stabilizer is lithium.
 24. The composition of claim 22,wherein aripiprazole is anhydrous aripiprazole crystals B.
 25. Thecomposition of claim 21, wherein the at least one compound isaripiprazole and the at least one mood stabilizer is valproic acid ordivalproex sodium.
 26. The composition of claim 21, wherein the at leastone compound is dehydroaripiprazole,2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)-butyl]-piperazin-1-yl}-phenylsulfate (DM-1458),7-{4-[4-(2,3-dichloro-4-hydroxyphenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2-(1H)-quinolinone(DM-1451),7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-4-hydroxy-2-(1H)-quinolinone(DM-1462),1β-(2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)-bulyl]-piperazin-1-yl}-phenoxy)-D-glucopyaranuronicacid (DM-1454) or 1-(2,3-dichlorophenyl)piperazine (DCPP) in combinationwith at least one mood stabilizer which is valproic acid or divalproexsodium.
 27. The composition of claim 25, wherein aripiprazole isanhydrous aripiprazole crystals B.